Author + information
- Carl J. Lavie, MD⁎ (, )
- James J. DiNicolantonio, PharmD,
- Richard V. Milani, MD and
- James H. O'Keefe, MD
- ↵⁎John Ochsner Heart and Vascular Institute, Ochsner Clinical School–The University of Queensland School of Medicine, 1514 Jefferson Highway, New Orleans, Louisiana 70121-2483
Being enthusiastic regarding the importance of high-density lipoprotein cholesterol (HDL-C) and the potential for HDL-C–raising therapies (1–3), we were disappointed in the outcomes of the early cholesterol ester transport protein inhibition trial with torcetrapib (4) as well as the recent AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial (5) with extended-release (ER) niacin. Although AIM-HIGH was the largest and most publicized niacin trial in decades, disappointing results may partly be due to limitations in the trial, including higher doses of simvastatin and greater use of ezetimibe (22% vs. 10%) in the statin-only compared with the statin/niacin arm, as well as the fact that the statin-only group actually received up to 200 mg of immediate-release niacin, and did have an increase in HDL-C (+9.8%) and a reduction in triglycerides (TGs) (−8.1%) and low-density lipoprotein cholesterol (LDL-C) (−5.5%) at 2 years. Also, the trial was stopped after only 36 months, which may have been too short term to notice benefits in patients with baseline LDL-C levels of only 71 mg/dl, realizing that the original Lipid Research Clinic–Coronary Prevention Trial with cholestyramine (6) and the 4S (Scandinavian Simvastatin Survival Study) with simvastatin (7) included patients with markedly higher levels of LDL-C (upper 190s mg/dl), and significant benefits were not noted until well after 3 years in these trials. Nevertheless, despite including AIM-HIGH in their meta-analysis, Lavigne and Karas's analysis (8) of 11 trials in 9,959 subjects in the recent issue of the Journal still reported reductions in major cardiovascular disease and coronary heart disease events of 34% (p = 0.007) and 25% (p = 0.02), respectively, with niacin therapy, potentially partly salvaging niacin's reputation as an effective preventive therapy in addition to its documented effects in raising HDL-C, and lowering TGs and LDL-C.
However, within days of this Journal publication, we learned that the recent Merck trial, HPS2-THRIVE (Heart Protection Study2—Treatment of HDL to Reduce Incidence of Vascular Events) with ER niacin combined with laropiprant, which blocks the niacin-induced flushing, was stopped. HPS2-THRIVE, the largest-ever niacin study, enrolling nearly 3 times the number of patients as in the Journal meta-analysis, failed to show a clinical benefit for niacin during a mean follow-up of 3.9 years and even found a strong signal of potential harm (9). Nevertheless, this trial included patients regardless of HDL-C levels, and the lack of benefit (or harm) may not be necessarily due to ER niacin but rather to laropiprant. We know that laropiprant mainly inhibits prostaglandin D2 (PGD2) from binding to PGD1 receptors. Although the flushing with niacin is mostly mediated by increasing PGD2, this prostaglandin also has important cellular metabolites that could provide additional mechanisms of benefit. Specifically, 15-deoxyprostaglandin J2, the main cellular metabolite of PGD2, is a potent endogenous ligand of peroxisome proliferator-activated receptor (PPAR)-gamma, so at least some of niacin's benefit may be mediated by stimulation of the PPAR receptor and thus potentially negated by laropiprant (10).
During the course of a single week, we witnessed a niacin flip-flop (benefit in the Journal meta-analysis  and lack of benefit and possibly slight harm in the large HPS2-THRIVE trial ) that has left clinicians in limbo. Clearly, further subgroup analyses of these major ER niacin trials (AIM-HIGH and HPS2-THRIVE), especially in subgroups most likely to benefit from niacin therapy (e.g., patients with combined very low levels of HDL-C and elevated TGs) are still needed, which may likely show benefits in these groups, similar to the benefits of fenofibrate in these subgroups, despite the otherwise overall negative results in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) lipid trial (11).
The niacin controversy continues, yet we believe that the results of this Journal meta-analysis of niacin's benefits (8) support the fact that niacin lives for another day, albeit possibly on life support. Indeed, niacin is still alive in preventive cardiology, but may need to be resuscitated in 2013.
Please note: Dr. Lavie is a speaker for and consultant to Abbott, Amarin, Upsher-Smith, Pfizer, and GlaxoSmithKline; and receives honoraria for his services. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Lavie C.J.,
- Milani R.V.
- Milani R.V.,
- Lavie C.J.
- Lavigne P.M.,
- Karas R.H.
- Husten L.